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Analysis of association between components of the folate metabolic pathway and autism spectrum disorder in eastern Indian subjects

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Abstract

Background

Folate has a pivotal role in maintaining different cellular processes including DNA integrity and neurotransmitter levels. Further, folate deficiency was reported in subjects with neuropsychiatric disorders including autism spectrum disorder (ASD).

Methods and results

We recruited ASD probands following the Diagnostic and Statistical Manual of Mental Disorder-IV/-5. Severity was assessed by the Childhood Autism Rating Scale2-Standard Test (CARS2-ST). Functional SNPs in reduced folate carrier1 (rs1051266), methylenetetrahydrofolate dehydrogenase (rs2236225), methylenetetrahydrofolate methyltransferase (rs1805087), methylenetetrahydrofolate reductase (rs1801133 and rs1801131), cystathionine-beta- synthase (rs5742905), and serine hydroxymethyltransferase (rs1979277) genes were analyzed in the ASD probands (N = 203), their parents and controls (N = 250) by PCR/TaqMan based methods. Plasma homocysteine and vitamin B12 levels were examined by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis revealed higher frequencies of rs1051266 and rs1805087 “A” alleles (P = 8.233e-005 and P = 0.010 respectively) and rs1051266 “AA” genotype (P = 0.02) in the ASD probands. Gender based stratified analysis revealed higher frequency of rs1051266 “AA” in the male probands (P = 0.001) while frequencies of rs1805087 “A” (P = 0.001) and “AA” (P < 0.05), and rs2236225 “CC” (P = 0.03) were higher in the females. The case–control analysis also exhibited a significant difference in the occurrence of biallelic and triallelic haplotypes. rs1051266 “A”, rs1979277 “T” and rs5742905 “C” alleles showed biased parental transmission (P = 0.02). CARS2-ST scores were higher in the presence of rs5742905 “T” while scores were lower in the presence of rs1979277 “T” and rs1051266 “A”. ASD probands showed vitamin B12 deficiency.

Conclusion

Based on these observations, we infer that components needed for proper folate metabolism may influence ASD severity in this population.

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Data availability

Data generated from the study are presented in tabular format. Further details are presented in Additional files. The sequences of SNP were obtained from the NCBI SNP database. Further details will be available from the corresponding author on reasonable request.

Abbreviations

ADHD:

Attention deficit hyperactivity disorder

ASD:

Autism spectrum disorder

CARS2-ST:

Childhood Autism Rating Scale 2-Standard Test

CBS:

Cystathionine beta synthase

ELISA:

Enzyme-linked immunosorbent assay

Hcy:

Homocysteine

HWE:

Hardy–Weinberg equilibrium

IG:

Information gain

LD:

Linkage disequilibrium

MDR:

Multifactor dimensionality reduction

MTHFD:

Methylenetetrahydrofolate dehydrogenase

MTHFR:

Methylenetetrahydrofolate reductase

MTR:

Methylenetetrahydrofolate methyltransferase

OR:

Odds ratio

PCR:

Polymerase chain reaction

QT:

Quantitative trait

RFC1:

Reduced folate carrier1

RFLP:

Restricted fragment length polymorphism

SHMT1:

Serine hydroxymethyltransferase

SNP:

Single nucleotide polymorphisms

TDT:

Transmission disequilibrium test

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Acknowledgements

The authors are thankful to the study participants for volunteering in the study. The authors are also obliged to the Indian Council of Medical Research, Govt. of India for funding the study.

Funding

This study was sponsored by the Indian Council of Medical Research, Govt. of India as an ad hoc research grant to KM & UR [GIA/37/2014-DHR]; KM was PI of the project. SS and TS were recruited under the project.

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Author notes

  1. Tanusree Saha

    Present address: Department of Microbiology, University of Alabama, Birmingham, USA

  2. Usha Rajamma

    Present address: Inter University Centre for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Kottayam, Kerala, India

Authors and Affiliations

  1. Manovikas Biomedical Research and Diagnostic Centre, Manovikas Kendra, 482 Madudah, Plot I-24, Sector J, EM Bypass, Kolkata, West Bengal, 700107, India

    Sharmistha Saha, Tanusree Saha, Usha Rajamma, Swagata Sinha & Kanchan Mukhopadhyay

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Contributions

Genotyping, data analysis, interpretation, and manuscript draft preparation were performed by SS. TS assisted in genotyping of control samples. UR was a co-investigator in the project. SS recruited ASD patients and provided clinical input. KM conceptualized the work, supervised study designing as well as data interpretation, and edited the manuscript. All the authors approved the final manuscript.

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Correspondence to Kanchan Mukhopadhyay.

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All the procedures performed involving human participants were approved by the institutional Human Ethical Committee (No. PR-006-14).

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Saha, S., Saha, T., Rajamma, U. et al. Analysis of association between components of the folate metabolic pathway and autism spectrum disorder in eastern Indian subjects. Mol Biol Rep 49, 1281–1293 (2022). https://doi.org/10.1007/s11033-021-06956-z

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